This invention relates to methods for making porous delivery devices, particularly pharmaceutical tablets.
Pharmaceutical tablets are often administered orally. A rapid disintegration of the tablet in the mouth without mastication or water facilitates administration to patients in general, and to the very young, the elderly, and to non-human animals, in particular.
One type of oral dosage form which is designed to address the problem of swallowing is known as "chewable tablets". These tablets, however, are not fully satisfactory because they require mastication.
Another type of oral dosage form known as the "effervescent tablet" comprises solid adjuvants of an acid and a base. The reaction between the acid and the base in the presence of water gives off carbon dioxide which "blows apart" the tablet to facilitate its dissolution. One type of effervescent tablet that must dissolve in a glass of water for administration requires that the patient drink the water. Aside from the problem of leaving a small amount of residual active agent in the glass, this dosing method is impractical for very young patients. Another type of effervescent tablet that "bubbles" and then dissolves in the mouth is also objectionable to some patient populations, especially the very young. Both types of effervescent tablets are thus not fully satisfactory.
Yet another type of oral dosage form known as the "enteric tablet" is designed to release the pharmaceutical agent in the upper small intestine. A limitation of enteric tablets is that those that fail to disintegrate rapidly in the intestine could pass the "window of absorption" and result in poor bioavailability.
One type of non-oral dosage form known as the birth control pessaries often takes as long as ten minutes to release the foaming agent. For obvious reasons, it is desirable for this type of dosage form to disintegrate rapidly. Tablets that disintegrate rapidly in an aqueous environment are often formulated with disintegration agents, such as starch, microcrystalline cellulose, carboxymethylcellulose sodium, and sodium starch glycolate, etc. These tablets disintegrate at an unsatisfactory rate for some applications described above.
An increased disintegration rate can be obtained by increasing the porosity (void spaces) of the tablet. Void spaces in the tablet matrix facilitate the permeation of water to rapidly erode the entire tablet. It is therefore desirable to obtain tablets of the highest porosity technically achievable.
U.S. Pat. No. 3,885,026 discloses a process for the production of porous tablets. In this process, a solid volatilizable adjuvant is incorporated in the tablet formulation. The tablet is formed by compression, and the volatilizable adjuvant is removed by sublimation or thermal decomposition. Exemplary volatilizable adjuvants include urethane, urea, ammonium bicarbonate, hexamethylenetetramine, benzoic acid, phthalic anhydride, naphthalene and camphor. The maximum porosity obtained according to this patent is 50% and preferably 10 to 30%. Tablets of high strength at a porosity higher than 50% are difficult to produce by this method.
U.S. Pat. No. 4,134,943 discloses the production of porous tablets by mixing the tablet components with a liquid solvent which is inert towards the tablet components. Suitable solvents include water, cyclohexane, benzene, etc., which freeze at a temperature from about -30.degree. to +25.degree. C. The solvent constitutes about 5 to 80% by weight of the total mixture. The mixture is divided or sprayed into small particles or droplets which are subsequently frozen into solid flowable granules. These granules are pressed into tablets at a temperature below the freezing point of the solvent, and then the solvent is sublimed from the tablets. The porosity of the resultant tablets corresponds to the amount of solvent that is removed from the tablet. The maximum porosity of the tablets produced by this method is 80%. The method of production in this patent is relatively complex since it involves the preparation of frozen granules.
Finally, U.S. Pat. Nos. 4,305,502 and 4,371,516 disclose the production of shaped articles by freezing, in a mold, a water-based pharmaceutical composition, and subliming the water from the frozen composition to form porous articles. Because the articles produced by this process have weak, easily broken meniscuses, U.S. Pat. No. 4,305,502 reduces the amount of handling of the articles by forming them in situ in the depressions of a filmic packaging substrate.
A commercial product based on U.S. Pat. No. 4,305,502 is known as R.P. Scherer's Zydis.TM.. A similar type of porous article known as Quicksolv.TM. by Mediventure Inc. (International Publication No. WO 91/09591) is made by a solvent exchange process which removes the water from the frozen matrix (instead of by lyophilization). Since both Zydis.TM. and Quicksolv.TM. are formed from an aqueous composition, pharmaceutical agents that are sensitive to water (because of stability or taste masking) are not suitable for these systems. In addition to the compatibility problem with aqueous compositions, the frozen matrix tends to stick to the mold in which the aqueous composition is frozen. This is in part due to the fact that water expands upon freezing. To facilitate the release of the product from molds, a surfactant is used in U.S. Pat. Nos. 4,305,502 and 4,371,516.
Although there are a variety of methods for making porous tablets, these methods do not adequately address all the problems. For example, the processes can be complex, the resultant tablets may lack sufficient porosity, the tablets may lack sufficient strength, the composition may be incompatible with the active agents, and the products may stick to the molds. Accordingly, there is a continual search in this art for methods for making highly porous, high strength, fast-dissolving tablets.